Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Area of Science:

• Immunology
• Metabolic pathways
• Neuroimmunology

Background:

• Dendritic cells (DCs) are crucial in controlling self-reactive T cells, making them therapeutic targets for autoimmune diseases.
• Understanding DC regulatory mechanisms is key to developing effective autoimmune therapies.

Approach:

• Utilized single-cell and bulk transcriptional and metabolic analyses.
• Performed cell-specific gene perturbation studies.
• Engineered a lactate-producing probiotic for therapeutic intervention.

Key Points:

• Identified a negative feedback loop in DCs involving lactate, HIF-1α, and NDUFA4L2.
• Lactate boosts NDUFA4L2 expression via HIF-1α, limiting mitochondrial reactive oxygen species.
• This pathway controls pathogenic T cells and suppresses T-cell autoimmunity in the CNS.

Conclusions:

• Discovered an immunometabolic pathway regulating DC function to prevent autoimmune pathology.
• Developed a synthetic probiotic to therapeutically activate this pathway for treating CNS autoimmunity.